The present invention is directed to novel methods of prostanoid synthesis. More specifically, the invention is directed to the addition of alpha chains to prostanoids using cis-alkenylstannane intermediates.
Naturally occurring prostaglandins are biologically active in a myriad of ways including hormone action, muscular contraction/relaxation, platelet aggregation/inhibition, intraocular pressure reduction and other cellular transduction mechanisms. Prostaglandins are enzymatically produced in nature from arachidonic acid. The arachidonic acid cascade is initiated by the prostaglandin synthase catalyzed cyclization of arachidonic acid to prostaglandin G2 and subsequent conversion to prostaglandin H2. Other naturally occurring prostaglandins are derivatives of prostaglandin H2. A number of different types of prostaglandins have been discovered including A, B, C, D, E, F and I-Series prostaglandins. These descriptions delineate substitution patterns of the various cyclopentane group central to all prostaglandins. Still other naturally occurring derivatives include thromboxane A2 and B2.
Due to their potent biological activity, prostaglandins have been studied for possible pharmaceutical benefit. However, due to potency of these molecules, as well as the ubiquitous presence of these agents and receptors and other biologically responsive tissue sites to their presence, numerous side effects have prevented the exploitation of the naturally occurring prostaglandins. It has also been difficult to pharmaceutically exploit the naturally occurring prostaglandins due to the relatively unstable nature of these molecules. As a result, researchers have been preparing and testing synthetic prostaglandin analogs, also known as xe2x80x9cprostanoids,xe2x80x9d for several decades.
In general, prostanoids can be described generically as consisting of (1) an alpha chain; (2) an omega chain; and (3) a cyclopentane group (or a heterocycle or other ring structure), as shown in formula I. 
In general, the E groups of the ring structure are independently O, CHxe2x80x94OH, Cxe2x95x90O, CH-halogen and CH2 groups. The omega chain has generally consisted of linear carbon backbones of varying lengths. The omega chains have also been of varying degrees of saturation, containing optional hetero-atoms and have terminated with a variety of alkyl and cycloalkyl groups. Alpha chains have consisted of numerous linear moieties and have involved various degrees of saturation. The alpha chains generally consist of a seven carbon chain and generally terminate with a carboxylic acid group or a variety of corresponding esters.
Of particular interest are a set of prostanoids having a double bond at carbons 5 and 6 and an oxygen or carbon at the three position, according to formula II: 
wherein, the E groups are as defined above; A is oxygen or carbon; Q is H or C1-4 alkyl: and the omega chain (xcfx89) is generally five to twelve carbons in length with various substitutions including substitutions of hetero-atoms within the chain.
As summarized in Scheme A, prostanoids of formula II can be prepared by reacting a methylene ketone 1 with a cis-alkenylcuprate 2 to install the alpha chain and thereby form the cis-alkenyl intermediate 3, wherein X is O, CH2, CHxe2x80x94OH (or CHxe2x80x94O-protected), xcfx89 is as defined above, R is generally a nontransferring group, Rxe2x80x2 is generally a hydroxyl protecting group and Zxe2x80x2 is generally a masked carboxyl group. 
The cis-alkenylcuprate 2a or 2b can be one of several different types known to those skilled in the art. Homocuprates bear two identical carbon groups bonded to copper, only one of which can efficiently form a carbon-carbon bond by transfer from copper, the remaining group being by definition the nontransferring group R. Heterocuprates bear two different carbon groups bonded to copper, one of which (R) has a low tendency to form a carbon-carbon bond compared with the transferring group, in this case the cis-alkenyl group. Higher-order cuprates contain a metal cyanide salt, typically LiCN. Lower-order cuprates do not contain metal cyanide salts but can contain other components capable of modifying reactivity, for example, a trialkylphosphine. The cis-alkenylcuprates of formulas 2a and 2b are optionally associated with a metal cyanide salt or other component. See, generally, Lipshutz, Organic Reactions, volume 41, page 135 (1992).
Stork and Isobe, J. Am. Chem. Soc., volume 97, page 4745 (1975), disclose a method of preparing racemic 3-carba prostanoids as shown in Scheme A, wherein X is CHOCH2Ph (in the rel-R configuration), xcfx89 is trans-CHxe2x95x90CHCH(OCH2OCH2Ph)-n-C5H11, Zxe2x80x2 is CH2OCH(Me)OEt, and the cis-alkenyl cuprate 2a is the lower-order homocuprate cis-(EtOCH(Me)O(CH2)4CHxe2x95x90CH)2CuLi.PBu3. The cis-alkenylcuprate 2a was prepared from the cis-iodoalkene cis-EtOCH(Me)O(CH2)4CHxe2x95x90CHI by lithium-iodine exchange with tert-butyllithium, forming the intermediate cis-alkenyllithium compound cis-EtOCH(Me)O(CH2)4CHxe2x95x90CHLi, which was then reacted with CuIxe2x80x94PBu3 complex to yield 2a.
Sato, Tetrahedron: Asymmetry, volume 3, page 1525 (1992), discloses a method of preparing nonracemic 3-oxa prostanoids as shown in Scheme A, wherein X is CHOSiMe2t-Bu (in the R configuration), xcfx89 is trans-CHxe2x95x90CHCH(OSiMe2t-Bu)-cyclo-C6H11 (in the S configuration), Rxe2x80x2 is CH(Me)OEt, and the cis-alkenylcuprate 2b is the higher-order heterocuprate cis-EtOCH(Me)OCH2CHxe2x95x90CHCu(2-thienyl)Li.LiCN. The cis-alkenylcuprate 2b was prepared from the cis-iodoalkene cis-EtOCH(Me)OCH2CHxe2x95x90CHI by lithium-iodine exchange with tert-butyllithium, forming the intermediate cis-alkenyllithium compound cis-EtOCH(Me)OCH2CHxe2x95x90CHLi, which was then reacted with (2-thienyl)Cu(CN)Li to yield 2b.
The cis-iodoalkene to cis-alkenyllithium to cis-alkenylcuprate sequence employed in the foregoing examples has several disadvantages. The preparation of cis-iodoalkenes typically involves reaction of a 1-iodoalkyne with diimide, which is not suitable for large scale work and always produces some 1-iodoalkane; see Luthy, J. Am. Chem. Soc., volume 100, page 6211 (1978). Other methods of preparing cis-iodoalkenes give variable amounts of the trans isomer, see Dieck, J. Org. Chem., volume 40, page 1083 (1975), and Stork and Zhao, Tetrahedron Letters, volume 30, page 2173 (1989). The reagent of choice for converting the cis-iodoalkene to the cis-alkenyllithium has been tert-butyllithium, which is pyrophoric and not suitable for large scale work. This conversion must be performed at low temperature, typically xe2x88x9260xc2x0 C. or below, in order to realize good yields.
Transmetalation methods have been described in the art. For example, U.S. Pat. No. 4,777,275 (Campbell et al.) discloses a direct tin-to-copper transmetalation. In that disclosure, a trans-alkenylstannane is directly converted to a trans-alkenylcuprate, which is used for the addition of a trans omega chain to a prostanoid.
A need has arisen, therefore, to develop superior synthetic methods for the preparation of the various prostanoids of interest, in greater yields.
The present invention is directed to methods of prostanoid synthesis. More specifically, the invention is directed to methods involving cis-alkenylstannanes for prostanoid alpha chain addition.
The use of cis-alkenylstannanes obviates problems existing with traditional synthetic methods involving treatment of cis-iodoalkenes with alkyllithiums to form cis-alkenyllithiums, which are then converted to cis-alkenylcuprates. The avoidance of the cis-iodoalkene and cis-alkenyllithium intermediates minimizes unwanted side products and also allows for greater yield of key intermediates useful in prostanoid synthesis.
Preferred methods of the present invention employ the novel intermediate synthesis of the present invention in the synthesis of 3-oxa prostanoids.
The present invention is directed to novel methods of prostanoid synthesis. More specifically, the present invention is directed to methods of improved prostanoid alpha chain addition to form prostanoids of formula III: 
wherein,
X is O, CH2, Cxe2x95x90O, or CHxe2x80x94OR4 in either configuration, or CH-halogen (F, Cl, Br, I) in either configuration;
A is CH2 or O;
Q is H or C1-4 alkyl;
R3 is H and one of: H, OR4, halogen, in either configuration, or, R3 is xe2x95x90O (i.e., carbonyl);
R4 is H, alkyl, acyl, or Si(R6)3, wherein R6 is independently C1-4 alkyl or phenyl;
provided that when R3 is xe2x95x90O, X is not CH-halogen, and when R3 is H and halogen, X is not Cxe2x95x90O;
xcfx89 is 
xe2x80x83wherein:
---- is an optional bond;
D is H and one of: H, F or OR4, in either configuration; or D is xe2x95x90O (i.e., carbonyl);
X1 is (CH2)m or (CH2)mO, wherein m is 1 to 6; or Xxe2x80x2 is CHxe2x80x94OH; and
Y is a phenyl ring optionally substituted with alkyl, halo, trihalomethyl, alkoxy, acyl, acyloxy, amino, alkylamino, acylamino, or hydroxy; or Y is C1-6 alkyl or C3-8 cycloalkyl, optionally substituted with C1-6 alkyl, or
X1xe2x80x94Y is (CH2)pYxe2x80x2; wherein p is 0 to 6; and 
xe2x80x83wherein:
W is CH2, S(O)q, NR5, CH2CH2, CHxe2x95x90CH, CH2O, CH2S(O)q, CHxe2x95x90N, or CH2NR5;
wherein q is 0 to 2, and R5 is H, alkyl, or acyl;
Z is H, alkyl, alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, alkylamino, acylamino, or hydroxy; and
---- is an optional bond; or
Xxe2x80x2xe2x80x94Y is C1-6 alkyl, or C3-8cycloalkyl.
Preferred prostanoids synthesized with the methods of the present invention are those of formula III having an xcfx89 chain consisting of: 
wherein T is CF3 or Cl, and R4 is defined as above. Most preferred are those compounds wherein 4 is hydrogen.
The improved alpha addition methods of the present invention are illustrated in Scheme B. 
wherein X is O, CH2, CHxe2x80x94OH (or CHxe2x80x94O-protected), and 1, 3a, 3b, are defined as is above.
The cis-alkenylcuprate 6a or 6b is prepared by transmetalation of a cis-alkenylstannane 4a or 4b, respectively, by reaction with a cuprate reagent 5. The R groups of 5 are chosen so that the transmetalation of 4 to 6 proceeds efficiently, and so that in the subsequent reaction of 6 with 1, the R group of 6 is a nontransferring group, for example an alkyl group. The tin-to-copper transmetalation reaction can be performed in several different ways. For example, dilithium (dimethyl)cyanocuprate (5, R is methyl) can be reacted with the cis-alkenylstannane 7 in a solvent such as tetrahydrofuran, diethyl ether, an aromatic hydrocarbon or mixtures thereof. This reaction proceeds efficiently at a temperature of about 0 to 25xc2x0 C. The resulting cis-alkenylcuprate 6 is then reacted with the exo-methylene ketone 1 to yield the cis-alkenyl intermediate 3.
For the preparation of 3-carba prostanoids, the cis-alkenylstannane 4a is of the formula cis-Rxe2x80x33SnCHxe2x95x90CH(CH2)3Zxe2x80x2 wherein Rxe2x80x3 is C1 to C6 alkyl, preferably methyl or n-butyl, and most preferably n-butyl, Zxe2x80x2 is a functional group capable of being converted to COOH, and compatible with the conditions of the tin-to-copper transmetalation reaction used to prepare the cis-alkenylcuprate 2a, for example, an ortho ester, acetal, or protected carbinol, as generally known to those skilled in the art. The compound cis-Rxe2x80x33SnCHxe2x95x90CH(CH2)3Zxe2x80x2 can be prepared by the general method described by Corey, Tetrahedron Letters, volume 25, page 2419 (1984), involving copper-catalyzed coupling of cis-Rxe2x80x33SnCHxe2x95x90CHCH2OAc with a Grignard reagent (Hal)Mg(CH2)3Zxe2x80x2, wherein Hal=Cl, Br or I, and Zxe2x80x2 is defined as above.
For the preparation of 3-oxa prostanoids, the cis-alkenylstannane 4b is of the formula cis-Rxe2x80x33SnCHxe2x95x90CHCH2ORxe2x80x2 wherein Rxe2x80x3 is defined as above, and Rxe2x80x2 is a protecting group compatible with the conditions of the tin-to-copper transmetalation reaction used to prepare the cis-alkenylcuprate 2b, for example, substituted silyl, tetrahydropyranyl, or 1-ethoxyethyl. The compound cis-Rxe2x80x33SnCHxe2x95x90CHCH2ORxe2x80x2 can be prepared by appending a protecting group to cis-Rxe2x80x33SnCHxe2x95x90CHCH2OH, the preparation of which is known wherein Rxe2x80x3 is n-butyl; see Corey, above. Alternatively, cis-Rxe2x80x33SnCHxe2x95x90CHCH2ORxe2x80x2 can be obtained by hydrozirconation of an alkynylstannane; see Lipshutz, Tetrahedron Letters, volume 33, page 5861 (1992).
The cis-alpha chain intermediate 3b (generated from the novel methods of the present invention), can be converted to the 3-oxa prostanoids of formula III, wherein A is O, and R, Rxe2x80x2Rxe2x80x3 and xcfx89 are defined as above, by employment of known methods in the art, for example, the sequence generally described by Sato, above, and as summarized in Scheme C, below. Accordingly, reduction of the keto group of 3b (wherein X is CHOSiMe2t-Bu (in the R configuration), xcfx89 is CH2CH2CH(OSiMe2t-Bu)-cyclo-C6H11 (in the R configuration), and Rxe2x80x2 is CH(Me)OEt) gives alcohol 7. Removal of the protecting group CH(Me)OEt, from 7 (by known methods, e.g., Greene et al., Protective Groups in Organic Synthesis, 2nd ed., Wiley: New York, 1991) gives diol 8. Alkylation of 8 with tert-butyl bromoacetate gives the protected 3-oxa prostanoid 9. The OH group of 9 is substituted, via the methanesulfonate, with chloride to give the protected 9-chloro-3-oxa prostanoid 10. Removal of protecting groups from 10 provides the 9-chloro-3-oxa prostanoid 11. Further processing can be employed to give an analog of 11 containing an alpha chain terminating ester of choice, preferably isopropyl ester. 
As stated above, the methods of the present invention are also useful in preparing the 3-carba prostanoids of formula III, wherein A is CH2. For example, Stork and Isobe, above, disclose a method of converting a compound of Formula 3a, wherein X is CHOCH2Ph (in the rel-R configuration), xcfx89 is trans-CHxe2x95x90CHCH(OCH2OCH2Ph)C5H11 (in the rel-S configuration) and Zxe2x80x2 is CH2OCH(Me)OEt, into racemic prostaglandin F2xcex1, i.e., the compound of formula III wherein A is CH2, R3 is xcex2-H, xcex1-OH, X is CHxe2x80x94OH (in the rel-R configuration), Q is H and xcfx89 is trans-CHxe2x95x90CHCH(OH)-n-C5H11 (in the rel-S configuration). A further example is shown in Scheme D. Reduction of the keto group of the compound of formula 3a (wherein X is CHOSiMe2t-Bu (in the R configuration), xcfx89 is trans-CHxe2x95x90CHCH(OSiMe2t-Bu)CH2OC6H4-m-CF3 (in the R configuration), and Zxe2x80x2 is an OBO ester group (see Corey, above) gives alcohol 12. Hydrolysis of the OBO ester group of 12 yields the protected 3-carba prostanoid 13. Removal of protecting groups from 13 yields the free 3-carba prostanoid 14. Further processing can be employed to give an analog of 14 containing an alpha chain terminating ester of choice, preferably, isopropyl ester. 